(537.7) A New Family of Subnanomolar inhibitors of Soluble Epoxide Hydrolase

Poster Board Number: B83

Carmen Escolano (Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona and IBUB), Andrea Bagan (Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona and IBUB), Andreea Turcu (Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona and IBUB), Christophe Morisseau (UC Davis Comprehensive Cancer Center, University of California), M. Loza (Drug Screening Platform/Biofarma Research Group, CIMUS Research Center. University of Santiago de Compostela (USC)), Jose Brea (Drug Screening Platform/Biofarma Research Group, CIMUS Research Center, University of Santiago de Compostela (USC)), Clara Bartra (Institut d’Investigacions Biomèdiques de Barcelona (IIBB), CSIC and IDIBAPS), Coral Sanfeliu (Institut d’Investigacions Biomèdiques de Barcelona (IIBB), CSIC and IDIBAPS), Bruce Hammock (UC Davis Comprehensive Cancer Center, University of California), Santiago Vázquez (Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona and IBUB)

The pharmacological inhibition of soluble epoxide hydrolase (sEH) has been suggested as a potential therapy for the treatment of pain and inflammatory diseases through the stabilization of epoxyeicosatrienoic acids, endogenous chemical mediators derived from arachidonic acid that show anti-inflammatory and analgesic effects.1

Although several potent sEH inhibitors (sEHI) have been developed, including clinical candidates AR9281, GSK2256294, and EC5026, so far no sEHI has reached the market.2

Recently, a new series of benzohomoadamantane-based ureas endowed with potent inhibitory activity for the human and murine sEH was reported. However, their very low microsomal stability prevented further development.3

Herein, novel series of benzohomoadamantane-based ureas were synthesized, fully characterized, and evaluated as sEHI. Most of them were endowed with subnanomolar inhibitory potencies at the human and murine enzymes. Further in vitro profiling (solubility, cytotoxicity, metabolic stability, CYP450s, hLOX-5, hCOX-2, hERG inhibition, permeability) allowed us to select a candidate for efficacy studies.

In summary, these novel results and the previously reported studies using other families of sEHI, strongly suggest that sEH may be a target of clinical interest for the treatment of inflammatory and pain-related disorders.4

References:
1-Morisseau, C.; Hammock, B. D. Annu. Rev. Pharmacol. Toxicol. 2013, 53, 37–58.
2-Sun, C.-P.; Zhang, X.-Y.; Morisseau, C.; Hwang, S. H.; Zhang, Z.-J.; Hammock, B. D.; Ma, X.-C. J. Med. Chem. 2021, 64, 184–215.
3-Codony, S.; Calvó-Tusell, C.; Valverde, E.; Osuna, S.; Morisseau, C.; Loza, M. I.; Brea, J.; Pérez, C.; Rodríguez-Franco, M. I.; Pizarro-Delgado, J.; Corpas, R.; Griñán-Ferré, C.; Pallàs, M.; Sanfeliu, C.; Vázquez-Carrera, M.; Hammock, B. D.; Feixas, F.; Vázquez, S. J. Med. Chem., 2021, 64, 5429–5446.
4-McReynolds, C.; Morisseau, C.; Wagner, K.; Hammock, B. D. Adv. Exp. Med. Biol. 2020, 1274, 71–99.

This research was funded by Grants PID2020-118127RB-I00 and PID2019-107991RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by amp;ldquo;ERDF A way of making Europeamp;rdquo; to S.V. and C.E. Financial support from lt;igt;Generalitat de Catalunyalt;/igt; (2017 SGR 106) and lt;igt;Fundaciamp;oacute; Bosch i Gimpera, Universitat de Barcelonalt;/igt; (F2I grant), to S.V., and from the Xunta de Galicia (ED431G 2019/02 and ED431C 2018/21) to M.I.L. are acknowledged. Partial support was provided by NIH-NIEHS River Award R35 ES03443, NIH-NIEHS Superfund Program P42 ES004699, NINDS R01 DK107767, and NIDDK R01 DK103616 to B.D.H.